The overall goals of this Program Project are to understand the genetic bases for the pleiotropic phenotype of Down Syndrome (DS) by expanding the known genetic and physical maps of human Chromosome (Chr) 21, trisomeric in DS; analyzing their expression, function and relation to phenotype; and developing and using mouse model to study gene function and to provide test systems for therapies. The Jackson Laboratory Projects focuses on the development and use of mouse models for DS. Most genes on human Chr21 are conserved in distal mouse Chr 16. Based on the genes mapped so far in this segment, it appears to be conserved intact in human Chr21 and mouse 16. The remainder are on mouse Chrs 10 and 17. Previous mouse models that took advantage of the house 21-mouse 16 homology either died in utero (complete trisomy 16) or were not genetically reproducible from one mouse to another (chimeric trisomy 16<-->euploid mice). We have created a transmissible segmental trisomy, Ts(1716)65Dn, which carries three copies of most human Chr 21-homologous genes present on mouse Chr16. Our goals are to (1) analyze embryonic expression patterns of relevant genes identified in the Program Project, (2) improve the Ts65Dn model by combining it with duplications of mouse Chr 17 containing human Chr 21-homologous genes, (3) assess the phenotypic effects of genes affecting neuronal ion channels by musing mouse Chr 16 deletions to return specific Ts65Dn triplicated genes to disomy, and (4) analyze electrophysiological effects of these manipulated genes. We will (1) continue to analyze the expression of human Chr 21-homologous genes to determine normal expression patterns during development and to assess expression levels in Ts65Dn; (2) create additional mouse models with defined genetic backgrounds and additional or deleted mouse Chrs 17 and 16 genes, respectively; (3) compare the phenotypic and pathologic features of the strains in Aim 2 to the baseline already established for Ts65Dn; (4) do preliminary electrophysiological analysis of a subset of the mice produced by others in the Program Project alone or in combination with Ts65Dn, and (5) continue genetic mapping in the mouse of novel genes identified and analyzed by the Gene Identification Core.